Solution-State Polymer Assemblies Influence BCS Class II Drug Dissolution and Supersaturation Maintenance

Abstract

Spray dried dispersions (SDDs), solid dispersions of polymer excipients and active pharmaceuticals, are important to the field of oral drug delivery for improving active stability, bioavailability, and efficacy. Herein, we examine the influence of solution-state polymer assemblies on amorphous spray-dried dispersion (SDD) performance with two BCS II model drugs, phenytoin and probucol. These drugs were spray dried with 4 model polymer excipients consisting of poly(ethylene-alt-propylene) (PEP), N,N,-dimethylacrylamide (DMA), or 2-methacrylamido glucopyranose (MAG): amphiphilic diblock ter- and copolymers, PEP-P(DMA-grad-MAG) and PEP-PDMA, and their respective hydrophilic analogues, P(DMA-grad-MAG) and PDMA. Selective and nonselective solvents for the hydrophilic block of the diblock ter- and copolymers were used to induce or repress solution-state assemblies prior to spray drying. Prespray dried solution-state assemblies of these four polymers were probed with dynamic light scattering (DLS) and showed differences in solution assembly size and structure (free polymer versus aggregates versus micelles). Solid-state structures of spray dried dispersions (SDDs) showed a single glass transition event implying a homogeneous mixture of drug/polymer. Crystallization temperatures and enthalpies indicated that the drugs interact mostly with the DMA-containing portions of the polymers. Scanning electron microscopy was used to determine SDD particle size and morphology for the various polymer-drug pairings. In vitro dissolution tests showed excellent performance for one system, spray-dried PEP-PDMA micelles with probucol. Dissolution structures were investigated through DLS to determine drug-polymer aggregates that lead to enhanced SDD performance. Forced aggregation of the polymer into regular micelle structures was found to be a critical factor to increase the dissolution rate and supersaturation maintenance of SDDs, and may be an attractive platform to exploit in excipient design for oral drug delivery.

Adsorption of Polyvinylpyrrolidone and its Impact on Maintenance of Aqueous Supersaturation of Indomethacin via Crystal Growth Inhibition

“…Drug nucleation and crystal growth may be influenced by the intermolecular interactions between PPI and drug molecules in the bulk solution . For example, the effectiveness of PPIs in inhibiting the formation of carbamazepine dihydrate was related to the intermolecular hydrogen bonding and hydrophobic interactions between PPIs and carbamazepine but their relative impact on the effectiveness of a given PPI could not be determined because of the experimental limitations .…”

“…Drug nucleation and crystal growth may be influenced by the intermolecular interactions between PPI and drug molecules in the bulk solution. [11][12][13][14] For example, the effectiveness of PPIs in inhibiting the formation of carbamazepine dihydrate was related to the intermolecular hydrogen bonding and hydrophobic interactions between PPIs and carbamazepine but their relative impact on the effectiveness of a given PPI could not be determined because of the experimental limitations. 11 In another study, the superiority of HPMC-AS HF over HPMC-AS LF, two different grades of HPMC-AS containing different ratios of acetate and succinate substituents, in inhibiting the precipitation of carbamazepine from an aqueous solution was attributed to stronger hydrophobic interactions between HPMC-AS HF and carbamazepine in the bulk solution.…”

High-Throughput Excipient Discovery Enables Oral Delivery of Poorly Soluble Pharmaceuticals

“…16−19 In our studies, subtle molecular attributes that influence supersaturation such as amphiphilicity, ionic character, and related chemical properties have been identified. However, these functionalities are unable to maintain high supersaturation of drugs with fast recrystallization kinetics.…”

Bioavailability Improvement Strategies for Poorly Water-Soluble Drugs Based on the Supersaturation Mechanism: An Update

“…Similar results showed that HPMCAS systems performed better than or at least comparably to PVPVA systems, regardless of the drug loading or dose (23). Additionally, site-specific delivery could be obtained using enteric polymer HPMCAS or Eudragit L 100-55 (63,64).…”

“…Solid-state structures of spray-dried dispersions showed a single-glass transition of a homogeneous mixture of drug/polymer. Forced aggregation of the polymer into regular micelle structures was found to be a critical factor in increasing the dissolution rate and supersaturation maintenance of spray-dried SDs (63). Lyophilization is an alternative to develop rapid-dissolving formulations (73).…”